SummaryIn a recent study in rats, alanine am inotransferase (ALT ), the preferred plasma biomarker of hepatocellular injury in rats, was ineffective at detecting marked hepatic necrosis produced by acetam inophen (Hum a n a nd Expe rim e nta l To xic o lo gy 19, 277±83, 2000). In contrast, glutam at e dehydrogenase (GLDH) was markedly elevated. Accordingly, these enzymes were comprehensively evaluated as plasma biomarkers of hepatocellular injury in rats using several other models of hepatic injury, including partial hepatectom y and exposure to methapyrilene, dexamethasone, cyproterone, isoniazid, lead nitrate, and Wyeth-14643. Other enzymes also evaluated were aspartate aminotransferase (AST ), sorbitol dehydrogenase (SDH), and the hepatobiliary marker alk aline phosphatase (ALP). Compared to plasma ALT increases, plasm a GLDH increases were up to 10-fold greater, up to 3-fold more persistent, and occurred at tim es following hepatocellular injury when plasma ALT was not increased. Plasma GLDH act ivity was not inhibited by the test compounds, whereas ALT was substantially inhibited by both isoniazid and lead nitrate. While plasma GLDH activity was unaffected by induction, ALT was induced by cyproterone and dexamethasone, and ALP was induced by Wyeth-146 43 and partial hepatectomy. GLDH was concluded to be a more effective biom ark er of acute hepatic injury than ALT, AST, SDH or ALP in the rat, based primarily on the large increase following hepatocellular injury, prolonged persistence in the blood following injury, high sensitivity for detection of injury (including pre-necrotic injury), high tissue speci®city, and lower susceptibilit y to inhibition or induction.Keywords Glutamate dehydrogenase; rat; liver; plasm a; hepatotoxicity Drug-induced hepatocellular injury is most commonly evaluated in preclinical and clinical studies using alanine am inotransferase (ALT ) (Travlos e t a l. 1996, Fujii 1997 ). However, in the rat this enzym e has theoretical disadvantages as a hepatic biomark er since it has a relatively low intra-hepat ic activit y and short half-life in blood compared with that in the dog, monkey, and man (Evans 1996, Davy e t a l. 1988). Furthermore, literature review (Fujii 1997 ) and a recent study (O'Brien e t a l. 2000) indicate that in the rat , plasma ALT may fail to indicate hepatic necrosis.Glutamate dehydrogenase (GLDH; EC 1.4.1.3 ), a key enzyme in amino acid oxidation and urea production, has several features which mak e it at tract ive as a potential biomarker of drug-induced hepatocellular toxicity. It is highly conserved in structure, tissue-distribution, and function across a wide range of species (Schmidt & Schmidt 1988 ). In common with ALT, GLDH is a relatively liver-speci®c enzym e (Clam pitt 1978, Lindena e t a l. 1986 ); however, intracellular distribution is different. ALT is cytosolic in origin, whereas GLDH is located in the mitochondrial matrix (Zim merman 1974, Schmidt & Schmidt 1988
This report demonstrates the advantage s of using a noninvasive soft tissue imaging technique-magnetic resonance imaging (MRI)-to monitor liver regeneration after 70% partial hepatectomy in the rat in a longitudinal manner. Six animals were scanned prior to and on 6 subsequen t occasions up to 9 days after surgical removal of the median and left lateral lobes. Within the observed time frame liver volumes were restored to approximately 88% of presurgery values. The rate of regeneration was maximal at 1.5 days, which coincided with the maximum increase of Mitotic Index-a measure of cell proliferation, determined in a subsequen t study. Pre-and postpartial hepatectomy measurements remove two potentially confoundin g unknowns -the presurgery liver volume, and the amount of liver actually excised. 3D reconstruction s of the liver effectively illustrate the morphologica l changes associated with the procedure, and the regrowth of liver tissue.
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